Clinical manifestations

Presentation and course

Rocky Mountain spotted fever. In the United States, Dermacentor variabilis (dog tick) is the vector for most cases of Rocky Mountain spotted fever. This tick is found in the Eastern and Central parts of the United States as well as the Pacific Coast. D andersoni (wood tick) is the vector in the Western United States. Rhipicephalus sanguineus (brown dog tick) is a vector in parts of Arizona, Southern California, along the US–Mexico border, and in Mexico (03). Several species of Amblyomma ticks are the vector of Rocky Mountain spotted fever in Mexico and Argentina (03).

Symptoms of Rocky Mountain spotted fever typically begin 3 to 12 days after the bite of an infected tick; the incubation period is shorter in individuals with severe disease (03). Early symptoms of Rocky Mountain spotted fever are nonspecific and include high fever, headache, myalgias, and gastrointestinal symptoms. The characteristic rash begins 2 to 4 days after the onset of fever, but most patients present for care before rash onset; the classic triad of tick bite, rash, and fever is uncommon at first presentation (03). The rash begins as pink, blanching or nonblanching macules on the wrists and ankles and progresses to a maculopapular rash on the torso.

The rash may subsequently become petechial or purpuric. In severe cases, it may be ecchymotic and necrotic, especially in distal areas, including the fingers, toes, nose, ears, and genitals (49). Rash is more common and occurs earlier in the disease course in children than in adults. According to the Tennessee Unexplained Encephalitis Project, the median time to rash after fever onset was 1 day in children and 15.5 days in adults; rash was seen in all children and in only half of the adults (08).

The main neurologic complications of Rocky Mountain spotted fever are meningoencephalitis and cerebral edema (01), and clinical findings include altered mental status, focal abnormalities, increased tone, and reflex abnormalities. Seizures were seen in 42% of patients in the Tennessee Unexplained Encephalitis Project (08). Focal neurologic deficits, including cranial or motor neuropathies, and sudden transient hearing loss have been described (03).

Common laboratory findings in Rocky Mountain spotted fever include thrombocytopenia, anemia, hyponatremia, and increases in serum concentrations of aminotransferases, bilirubin, and creatine kinase (49; 03). Peripheral white blood cell concentration may be normal, but there may be an increase in immature granulocytes (03).

Anaplasmosis. Anaplasma phagocytophilum is transmitted by Ixodes scapularis ticks in the Northeast and Midwest United States and by Ixodes pacificus ticks on the West Coast. It is transmitted by I ricinus in Europe and by I persulcatus in Asia. The organism has an affinity for granulocytes, and it may also infect endothelial cells (43). Anaplasma can be transmitted by blood transfusion and organ transplantation, and infection may be more severe in these instances (37). The incubation period is 5 to 14 days (03). Symptoms are nonspecific and mimic those of Rocky Mountain spotted fever, including fever, headache, fatigue, arthralgia, and myalgia. However, contrary to Rocky Mountain spotted fever, rash is not typically seen. Neurologic manifestations are less common in anaplasmosis than in ehrlichiosis (03; 24). Confusion is the most common neurologic manifestation of infection (50). Young and Klein reported a patient who had both anaplasmosis and ehrlichiosis, with encephalopathy and frequent focal seizures (52). Stroke and cerebral vasospasm have been reported (29; 22; 38). Peripheral nervous system involvement, including brachial plexopathy; cranial nerve palsies, including bilateral facial palsy; and demyelinating polyneuropathy have been described in patients with anaplasmosis (24). Because of the overlap in tick vectors, concomitant infections with A phagocytophilum and B burgdorferi or Babesia microti in the United States (48; 24) or concomitant infection with A phagocytophilum and tick-borne encephalitis virus or B garinii in Europe (33; 34) have been reported.

Common laboratory findings in anaplasmosis include leukopenia, thrombocytopenia, and elevated serum levels of hepatic transaminases.

Ehrlichiosis. Ehrlichia chaffeensis is transmitted by Amblyomma americanum, the lone star tick (03), and this bacterium primarily infects monocytes. Ehrlichia chaffeensis infection is mostly seen in the Southeast, South Central, and mid-Atlantic United States, where the vector is endemic. Anaplasma can also be transmitted by blood transfusion and organ transplantation, and infection may be more severe in these instances (37). The incubation period is 5 to 14 days (03). Clinical symptoms of ehrlichiosis are nonspecific and mimic those of Rocky Mountain spotted fever and anaplasmosis, including fever, myalgia, headache, malaise, arthralgia, and nausea. Maculopapular, petechial, or red rashes are more common in ehrlichiosis than in anaplasmosis; they occur in up to 30% of patients, more commonly in children than in adults (48; 03; 24).

Ehrlichiosis is a more severe disease than anaplasmosis, and neurologic symptoms and signs are more common in ehrlichiosis than in anaplasmosis. Meningitis or meningovasculitis is seen in 20% of patients with ehrlichiosis (21). Other neurologic abnormalities include stupor and coma, hallucinations, seizures, and cranial nerve palsies (21).

Laboratory abnormalities in ehrlichiosis are similar to those of anaplasmosis, including leukopenia, thrombocytopenia, and increased serum concentration of hepatic transaminases.

African tick bite fever. Rickettsia africae is transmitted by Amblyomma ticks, and it is endemic in sub-Saharan Africa, the Caribbean, and Oceana. It is the most common cause of rickettsial disease in travelers, where it occurs in clusters (27; 17). Clinical symptoms typically develop 5 to 7 days after a tick bite but may take up to 10 days to develop (27). The clinical presentation mimics many of the manifestations of Rocky Mountain spotted fever, including fever, headache, and myalgia. Regional lymphadenitis and aphthous stomatitis may also be seen. Neck muscle pain with subjective stiffness is common, as it is in Rocky Mountain spotted fever (27). Unlike Rocky Mountain spotted fever, one or more inoculation eschars, which are characterized by a black crust surrounded by erythema, are a unique finding. Macular, papular, or vesicular rash near the eschar (27) is seen in about 40% of patients (45). The disease course is generally mild. Neurologic complications include neuropsychiatric symptoms in adults and encephalopathy in infants (45). Subacute neuropathy has been described as a complication in a small series (26).

Prognosis and complications

Of the rickettsial diseases discussed in this article, the death rate for spotted fever group rickettsiosis is the highest, at 5% to 10% (14). (Please note that the United States Centers for Disease Control and Prevention does not provide epidemiological data on Rocky Mountain spotted fever alone because of cross-reactivity among the spotted fever rickettsioses). Rocky Mountain spotted fever is commonly misdiagnosed at the first visit for medical care, and death is more likely when treatment is started more than 5 days after the onset of fever (30; 41). In addition to those with delayed treatment, children less than 10 years of age, adults 70 years or older, and individuals with alcohol use disorder or immunosuppression are at the greatest risk of death from Rocky Mountain spotted fever (18). Persons with G6PD deficiency can have early fulminant disease, leading to death (03). As with spotted fever rickettsioses, the elderly and those with underlying immunocompromise have poorer outcomes and are at the highest risk of death from anaplasmosis and ehrlichiosis (03). Children less than 10 years old have the highest case fatality rate for ehrlichiosis (03).

Neurologic involvement carries a poorer prognosis for all rickettsial infections, especially Rocky Mountain spotted fever (18). However, neurologic complications during acute disease may resolve, whereas patients may be left with permanent neurologic dysfunction (02). Long-term complications of Rocky Mountain spotted fever include cognitive impairment; hearing and vision loss; vestibular dysfunction; bowel and bladder abnormalities; and speech, motor, and cerebellar dysfunction; and seizures (03).

Biological basis

Etiology and pathogenesis

The gram-negative Rickettsiales, which include Rickettsia rickettsii and R africanus, Anaplasma phagocytophilum, and Ehrlichia chaffeensis, are obligate intracellular pathogens. They have reduced genomes, having lost the genes required to live outside of host cells (47). R rickettsia and R africanus grow and replicate in endothelial and vascular smooth muscle cell cytoplasm and cause a lymphohistiocytic vasculitis (27; 16). The infection is cytopathic, which can cause capillary leakage and systemic volume depletion.

A phagocytophilum and E chaffeensis have two intracellular forms: dense core cells and reticulate cells. Dense core cells are infectious and transform into reticulate cells that reside inside a membrane vacuole in the host cell. These vacuoles filled with bacteria are the morulae characteristic of infection. Unlike R rickettsii and R africanus, A phagocytophilum and E chaffeensis lack lipopolysaccharide and peptidoglycan, which enables them to evade host innate immune responses (24). Both incorporate host cholesterol (24).

For all four infections, interaction with target cells, be it vascular endothelium or leukocytes, leads to the secretion of proinflammatory cytokines and chemokines and recruitment of inflammatory cells. This inflammation is the main driver of pathogenicity (27; 47; 28). Excessive macrophage activation may lead to secondary hematophagocytic lymphohistiocytosis (HLH) in patients with anaplasmosis and ehrlichiosis, which may resolve with antibiotic therapy alone (39; 11; 44). Although this complication is uncommon in anaplasmosis, it may occur in at least 16% of individuals with ehrlichiosis (39; 11). Hematophagocytic lymphohistiocytosis is rarely reported in individuals with spotted fever rickettsiosis (23).

Unlike R rickettsia and R africanus, A phagocytophilum and E chaffeensis are not transmitted transovarially in ticks, so larval ticks are not infected. Infection of ticks with A phagocytophilum or E chaffeensis requires that they have a blood meal (48; 24).

Epidemiology

Rocky Mountain spotted fever. As of 2010, cases of Rocky Mountain spotted fever in the United States are reported under the category of spotted fever rickettsiosis because commonly available serological tests cannot distinguish between Rocky Mountain spotted fever and other rickettsial diseases that cause a similar illness (14). The reporting of all cases of rickettsial disease in the United States is passive, and its limitations should be acknowledged. Specifically, serological confirmation is required. A study using data from University of North Carolina Health showed that only 10% of individuals with suspected spotted fever group rickettsiosis underwent requisite acute and convalescent serological testing (see diagnostic workup below) (10). A study published in 2011 showed that the rate of reported Rocky Mountain spotted fever was as much as 11-fold higher in Native Americans than in whites (19). However, the odds of reporting Rocky Mountain spotted fever in Native Americans was almost 8-fold lower than in whites, likely reflecting limited access to health care and serological testing.

Limitations of surveillance aside, the number of reported cases of spotted fever rickettsiosis has increased over time (05; 14). However, the case fatality rate has decreased, perhaps because of the inclusion of spotted fever rickettsiosis infections caused by less virulent organisms compared to R rickettsii. Most cases are reported from April to September (03). The highest incidence of spotted fever rickettsiosis is in 60 to 69 year olds. The most recent data show that over half of the cases in the United States are reported from Arkansas, Missouri, North Carolina, Tennessee, and Virginia (14). Spotted fever rickettsioses are endemic in several Native American communities in Arizona (03), where delays in diagnosis have likely led to high mortality (41). Similarly, a large outbreak of Rocky Mountain Spotted Fever is ongoing in Mexicali, Mexico, and surrounding regions, which primarily impacts low income individuals (53). Recent increases in infections in Southern California have particularly impacted individuals who describe themselves as Hispanic or Latino and is likely related to the outbreak at the U.S.-Mexico border (31).

Anaplasmosis. Anaplasmosis was first seen in Switzerland and in Slovenia in 1997. It is now widespread in Europe and is seen in Russia, China, and South Korea (35). Anaplasmosis has been reportable in the United States since 1999, and the number of cases has successively increased since then (12). Although cases are reported year-round, most occur in the summer, which corresponds to when the nymphal ticks are active. A second, smaller peak occurs in the fall, when adult ticks are active (12). In the United States, anaplasmosis is seen in the Pacific Northwest, the Midwest, and the East Coast, with almost 90% of reported cases from Connecticut, Maine, Massachusetts, Minnesota, New Hampshire, New York, Vermont, and Wisconsin. Cases are most commonly reported in men and in persons over 40 years of age (12).

Ehrlichiosis. As of 2008, cases of E chaffeensis infection are separately reportable to the United States Centers for Disease Control and Prevention (13). The number of cases has successively increased since then. Although cases are reported throughout the year, most occur during the summer, with a peak in July. In the United States, E chaffeensis infections occur most frequently in the South Central, Southeastern, and mid-Atlantic United States. In 2019, nearly half of the cases were reported from Arkansas, Missouri, New York, and North Carolina (13).

African tick bite fever. African tick bite fever is endemic in sub-Saharan Africa, the Caribbean, and Oceania (15).

Prevention

There are currently no vaccines for the entities discussed in this article. Prevention measures include the avoidance of ticks for humans and their pets, rapid tick removal that avoids exposure to tick tissues and fluids, light-colored clothing when in known areas with ticks, and the use of effective repellants.

Differential diagnosis

Confusing conditions

The differential diagnosis of tick-borne rickettsioses is very broad (03). The primary consideration is bacterial sepsis, particularly meningococcemia. Other considerations include measles, secondary syphilis, idiopathic thrombocytopenic purpura, leptospirosis, infectious mononucleosis, arthropod-borne encephalitis, babesiosis, and Lyme disease. For returning travelers, the differential diagnosis for African tick bite fever includes malaria, typhoid, and other tropical fevers.

Diagnostic workup

Diagnosis primarily relies on clinical findings, especially if there is a history of exposure to the likely tick vectors. The rickettsial agents discussed in this article can be grown in tissue culture, but this diagnostic modality is not routinely available and may take 2 or more weeks; R rickettsii cultivation requires biosafety level 3 conditions (03). More widely available diagnostic tests include examination of a Wright or Giemsa-stained smear of blood; bone marrow or CSF for morulae in ehrlichiosis and anaplasmosis; acute and convalescent serology; and polymerase chain reaction testing of whole blood, cerebrospinal fluid, or tissue (especially for the spotted fever rickettsioses), including the eschar of African tick bite fever, which is the tissue of highest yield for diagnosis (27; 03; 17). Polymerase chain reaction is the preferred test because it can provide specific results quickly. Stain and polymerase chain reaction should be performed in the first week of illness when the yield is highest. On the other hand, immunofluorescent IgG serological tests are more likely to be positive 2 to 4 weeks after the onset of symptoms (48), which means that the studies may be negative early in the course of illness. An early negative immunofluorescent serological test should not dissuade providers from considering the diagnosis of rickettsial disease. The best way to use serological assays is to test together acute and convalescent serum samples collected 2 to 4 weeks apart (03). Serological tests for spotted fever rickettsia cannot distinguish between species.

In Rocky Mountain spotted fever, CSF may show very mild mononuclear pleocytosis and slightly elevated protein. Occasionally, the CSF glucose concentration may be low (08). Cerebrospinal fluid abnormalities are identified in 60% of patients with ehrlichiosis who have neurologic abnormalities, most commonly a mild (< 100 cells/ul) lymphocytic pleocytosis, although CSF cells may be neutrophils in 23% of individuals (21; 24). Morulae may uncommonly be identified in CSF monocytes (24).

Neuroimaging in Rocky Mountain spotted fever may show meningeal enhancement, cerebral infarctions, cerebral edema, or prominent perivascular spaces (07). A “starry sky” appearance on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted magnetic resonance images is described primarily in children with Rocky Mountain spotted fever, but may also be seen in adults (25). This imaging finding is likely due to small perivascular and deep white matter infarcts (32; 09; 08; 25). Imaging in patients with ehrlichiosis may show meningeal enhancement (24).

Management

Doxycycline is the treatment of choice for all patients with rickettsial disease, regardless of age or pregnancy, and it should be given empirically in the appropriate clinical setting without waiting for laboratory confirmation. Exposure to ticks or tick habitats; travel to endemic areas (keeping in mind that tick habitats are continuously evolving); or similar illnesses in family members, other contacts, or pets (especially dogs) can be a clue that supports the use of empiric therapy (48; 03). It is important to remember than many patients with rickettsial diseases will not report a tick bite. Moreover, a 1988 report of Rocky Mountain spotted fever acquired in the Bronx in New York, a nonendemic area, serves as a reminder that rickettsial disease should be suspected in any patient with an unexplained febrile illness given the ease of treatment and the risk of a poor outcome if treatment is delayed (46).

Recommended doxycycline dosages are 100 mg every 12 hours for adults and 2.2 mg/kg body weight twice a day for children under 45 kg. Doxycycline administration should continue until at least 3 days after fever resolves and clinical improvement is achieved for Rocky Mountain spotted fever, African tick bite fever, and ehrlichiosis (13; 14; 15). Treatment should be given for 10 days in patients with anaplasmosis because of the likelihood of concomitant B burgdorferi infection (03). Clinical improvement should be seen within 24 to 48 hours, and its absence suggests an alternative diagnosis or coinfection with an additional pathogen (48). Notably, an analysis of U.S. administrative claims data from 2005 to 2014 showed that overall, only 61% of individuals diagnosed with spotted fever group infection received recommended therapy (04).

Rickettsia species are sensitive in vitro to tigecycline (40). A report from Italy, where intravenous tetracycline is not available, describes successful treatment of four patients with meningoencephalitis and one patient with meningitis likely due to R conorii, the cause of Mediterranean spotted fever, with high dose intravenous tigecycline (36; 06). At this time there are no reported cases of human Rocky Mountain spotted fever treated with tigecycline.

Outcomes

Case fatality is 5% to 10% for spotted fever rickettsiosis combined (14). In a study of 80 hospitalized individuals with Rocky Mountain spotted fever in Arizona between 2002 to 2017, 17 (21%) died (20). Fifty-four of 63 survivors were impaired at hospital discharge based on modified Rankin score. Forty patients were interviewed after discharge, and nine of them underwent neurologic examination. Nine (23%) had persistent neurologic deficits, most commonly cognitive impairment. Some individuals with subsequent neurologic sequelae were reportedly normal at hospital discharge. The odds of neurologic sequelae were 19 times higher in patients who initiated doxycycline after day 5 of illness (20).

Case fatality rates are 0.3% in anaplasmosis (35), and 3% in ehrlichiosis (48). No deaths have been attributed to African tick bite fever (15). See Clinical manifestations and Prognosis and complications for more information.

Special considerations

Pregnancy

Doxycycline is the first-line treatment for suspected rickettsial disease in pregnant patients and in children. See Management for more information. In the case of life-threatening tetracycline allergy, desensitization should be considered.